Survivors of severe sepsis hospitalization have high long-term morbidity and mortality. More than one-half of all deaths that occur within one year after severe sepsis hospitalization happen after hospital discharge. Long-term consequences after sepsis will continue to increase with the rising incidence of sepsis and reduced short-term mortality after critical illness. An acute cardiovascular event, such as acute myocardial infarction and stroke, is an important long-term consequence of severe sepsis, occurring in 10% of patients discharged alive and accounting for one-third of deaths within one year. Of note, three-quarters of those who develop an acute cardiovascular event after severe sepsis do not have a prior history of cardiovascular disease and could be targeted for preventive therapies. However, the reasons for the link between sepsis and cardiovascular disease are not known. We recently showed that the immune response after pneumonia persists at hospital discharge despite clinical recovery, and higher circulating inflammatory and coagulation markers at discharge are associated with higher risk of subsequent cardiovascular deaths. The work proposed will extend our preliminary work and address four questions. First, with what frequency, and in which patients, does the immune response fail to resolve beyond discharge? Second, what might be the cause for delayed immune resolution? Third, are particular immune pathways more strongly associated with cardiovascular outcomes? Fourth, do early sepsis interventions have long-term beneficial effects? We will 'piggy-back' long-term follow-up in an ongoing randomized clinical trial designed to assess efficacy of Protocolized Care for Early Septic Shock, (ProCESS). We will enroll 600 ProCESS subjects who are alive at hospital discharge. We will conduct home visits to obtain blood and urine samples, and obtain all hospital records and conduct interviews with next of kin to determine fatal and non-fatal cardiovascular events over one year. Although many pathways are activated in sepsis, we will focus on 4 pathways (inflammation, coagulation-fibrinolysis, endothelial dysfunction, and oxidative stress) that are important in cardiovascular disease. For Aim #1, we will measure stable, well-validated circulating biomarkers in each pathway. We will test a novel hypothesis that the immune response initiated during severe sepsis will persist at discharge and at 3 weeks and 6 months after discharge, as evidenced by higher levels of biomarkers in these pathways. We will also conduct a small, exploratory study to asses if epigenetics will explain delayed resolution of the immune response. Aim #2 will determine whether unresolved immune response will increase the risk of acute cardiovascular events over 1 year after discharge. Aims #1 and #2 will identify biomarker patterns to target preventive therapies in future studies. Aim #3 will determine whether alternative cardiovascular resuscitation strategies that are known to affect the initial immune response will improve immune resolution after discharge and reduce late cardiovascular events. This work will result in one of the largest studies to date to assess recovery after sepsis, and the results will have immediate therapeutic implications to target patients with preventive strategies to reduce long-term consequences after sepsis. PUBLIC HEALTH RELEVANCE: Survivors of severe infections are at higher risk of developing a heart attack and stroke during the subsequent months, but underlying reasons are not known. The work proposed will determine circulating levels of inflammatory molecules during recovery from a severe infection as well as its relationship with subsequent development of a heart attack or stroke. We will also determine whether, for an infection, different treatment strategies implemented during the hospital course alter levels of inflammatory molecules after hospital discharge. This information is important to design future treatment plans toward improved health outcomes.